Lipid peroxidation for life extension?

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Taka

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Nov 8, 2009, 9:47:43 PM11/8/09
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Illustrating the Potency of Hormesis

Researchers are occasionally surprised when a genetic modification
expected to reduce life span in fact extends it. In this example, a
defense against lipid peroxidation is disabled in mice. (You might
recall that lipid peroxidation is one of the ways in which oxidative
damage originating in the mitochondria spreads throughout the body).
Rather than reducing the life span of these mice due to greater
damage, this actually has the effect of galvanizing further defensive
mechanisms to greater activity. So in fact, such a mouse winds up with
more effective repair and protection mechanisms over the long term.
This is an example of hormesis - regular application of a little
damage provokes an ongoing and massive response from the body's repair
mechanisms, which leads to a longer healthy life span. From the paper:
"The lipid peroxidation product 4-hydroxynonenal (4-HNE) forms as a
consequence of oxidative stress. ... A major route of 4-HNE disposal
is via glutathione conjugation, in the mouse catalyzed primarily by
glutathione transferase mGSTA4-4. Unexpectedly, mGsta4-null mice, in
which 4-HNE detoxification is impaired, have an extended life span.
This finding could be explained by the observed activation of the
transcription factor Nrf2 in the knockout mice, which in turn leads to
an induction of [a] detoxification mechanism that contributes to
enhanced longevity."

SOURCE: http://www.longevitymeme.org/news/vnl.cfm?id=4455


J Gerontol A Biol Sci Med Sci. 2009 Oct 30.

Disruption of the mGsta4 Gene Increases Life Span of C57BL Mice.

Singh SP, Niemczyk M, Saini D, Sadovov V, Zimniak L, Zimniak P.
Department of Pharmacology and Toxicology, #638, University of
Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock,
AR 72205.

The lipid peroxidation product 4-hydroxynonenal (4-HNE) forms as a
consequence of oxidative stress. By electrophilic attack on biological
macromolecules, 4-HNE mediates signaling or may cause toxicity. A
major route of 4-HNE disposal is via glutathione conjugation, in the
mouse catalyzed primarily by glutathione transferase mGSTA4-4.
Unexpectedly, mGsta4-null mice, in which 4-HNE detoxification is
impaired, have an extended life span. This finding could be explained
by the observed activation of the transcription factor Nrf2 in the
knockout mice, which in turn leads to an induction of antioxidant and
antielectrophilic defenses. Especially, the latter could provide a
detoxification mechanism that contributes to enhanced longevity. We
propose that disruption of 4-HNE conjugation elicits a hormetic
response in which an initially increased supply of 4-HNE is translated
into activation of Nrf2, leading to a new steady state in which the
rise of 4-HNE concentrations is dampened, but life-extending
detoxification mechanisms are concomitantly induced.
PMID: 19880816

Taka

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Nov 9, 2009, 3:35:45 AM11/9/09
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On Nov 9, 11:47 am, Taka <taka0...@gmail.com> wrote:
> Unexpectedly, mGsta4-null mice, in which 4-HNE detoxification is
> impaired, have an extended life span. This finding could be explained
> by the observed activation of the transcription factor Nrf2 in the
> knockout mice, which in turn leads to an induction of antioxidant and
> antielectrophilic defenses. Especially, the latter could provide a
> detoxification mechanism that contributes to enhanced longevity.

Perhaps this mechanism is behind the Japanese longevity attributed to
the consumption of (oxidized)fish and fish oil ...

Taka

http://www.bookmice.net/darkchilde/japan/jhimono.html

http://en.wikipedia.org/wiki/Katsuobushi


montygraham

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Nov 9, 2009, 2:43:58 PM11/9/09
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First of all, comparing mice to humans in a longevity context is at
best highly speculative. Secondly, why not just feed two groups of
mice diets that are very different? One would contain a great deal of
oil that is highly unsaturated and refined, while the other would get
fresh coconut oil. Then just see which group lives longer. Why
aren't they doing these kinds of studies, which are directly on point
and can't be "fudged?"

Third, most people are dying of cancer and "heart disease." In both
of these, products of highly reactive fatty acids are involved, the
best example being the molecules (such as LTB4 or PGE2) derived
directly from arachidonic acid. If you apply this notion (from the
study you cited) to humans, it could mean living to 120 rather than
115 or 110, but we all know that most people are going to die of
something else before that (again, heart disease and cancer will
likely strike them down). Thus, there seems to be little point to
this study, as it can't be "translated" directly to human experience,
and there is a much better experiment that should be done (and would
be cheap and easy to do, and in the case of mice, wouldn't take very
long either). I mostly ignore these kinds of studies now. There may
be something said that's worth investigating, but their direct claims
are often just plain laughable.

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